The BRCA1 gene is well known for its role in cancer susceptibility in part due to its high susceptibility to missense mutations. The gene encodes a large protein that regulates multiple functions within the cell; however the majority of these functions have only been described in mammary tissue. What is generally under-appreciated is the fact that BRCA1 expression patterns extend beyond female reproductive tissue. For example, we have found that BRCA1 is expressed in skeletal muscle, but at this time BRCA1 has no defined role in skeletal muscle. Here our goal is to use an integrative approach to delineate the mechanisms BRCA1 regulate in skeletal muscle. Our preliminary data demonstrate that loss of BRCA1 function in skeletal muscle through use of an inducible genetic ablation approach results in muscle weakness, kyphosis, exercise intolerance, and reduced mitochondrial function. The first specific aim will seek to determine if BRCA1 expression is critical for skeletal muscle function. The second specific aim will seek to determine if BRCA1 expression is necessary for mitochondrial function in skeletal muscle. The third specific aim will seek to determine if known missense mutations in the BRCA1 gene contribute to reduced skeletal muscle function. In this proposal we will use state-of-the-art physiological and molecular approaches as a means to elucidate the physiological mechanisms BRCA1 regulates in skeletal muscle. Since BRCA1 presents with a significant amount of genetic variation, understanding the mechanisms that BRCA1 regulates in skeletal muscle have the potential to aid in the prevention of conditions such as sarcopenia, physical disability, etc.